Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication
A number of compounds are effective in the treatment the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase is known for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. The (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one of formula (VI-i): ##STR2## is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one as a reverse transcriptase inhibitor, economical and efficient synthetic processes for its production need to be developed.
Thompson et al, Tetrahedron Letters 1995, 36, 937-940, describe the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition followed by cyclization with a condensing agent to form the benzoxazinone shown below. ##STR3## The p-methoxybenzyl aniline starting material is synthesized by benzylating the aniline nitrogen with p-methoxybenzyl chloride. Additionally, the overall process generates a large volume of heavy metal waste in the waste stream due to ceric ammonium nitrate oxidation in the debenzylation step.
European Patent Application 582,455 A1 describes the synthesis of benzoxazinones via a three step process. ##STR4## This general method teaches (1) metallation of the pivalamide of parachloroaniline with n-butyllithium followed by nucleophilic substitution with an ester to form a ketone, (2) synthesis of a tertiary carbinol by Grignard addition to the ketone, and (3) cyclization of the unprotected amine with the carbinol by addition of a large excess of condensing agent to form a benzoxazinone. The process requires further purification of the optical isomers through use of an optically active resolving agent such as (-)camphanic acid.
Young et al, PCT International Patent Application Number WO 9520389 A1 describe benzoxazinones useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. Application WO 9520389 A1 discloses methods of synthesis which are commensurate with EP 582,455 A1 above. Additionally, Young et al, Antimicrobial Agents and Chemotherapy 1995, 39, 2602-2605, in discussing the clinical benefit, the in vitro activity, and the pharmacokinetic activity of benzoxazinone (VI) in the treatment of HIV as an HIV reverse transcriptase inhibitor disclose an abbreviated synthesis of benzoxazinone (VI) commensurate with EP 582,455 A1 above wherein the tertiary carbinol is synthesized by addition of a cyclopropyl-ethynyl-lithium reagent before cyclizing the unprotected amine with the carbinol by addition of a condensing agent.
Thompson et al, PCT International Patent Application Number WO 9622955 A1 describe an improved synthesis of cyclopropylacetylene useful in the synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one. Application WO 9622955 A1 discloses combinations of synthetic methods disclosed in the publications above which continue to be inefficient in the overall synthesis for which this invention makes significant improvements.
The above methods for the syntheses of benzoxazinones use combinations of toxic, difficult to handle reagents, relatively expensive materials and inefficient chromatographic purification steps or generally overall synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one in low yields. Thus, it is desirable to discover new synthetic routes to benzoxazinones on a large scale which improve upon these limitations and provide high yields of desired benzoxazinones.
Accordingly, the present invention provides for a novel benzylating procedure, using acid catalyzed benzyl alcohols instead of the corresponding benzyl chloride analogues, which can be more expensive and unstable. Optimization of the procedure allows for streamlined processing since the product does not require isolation.
The present invention provides the preparation of (1R,2S)-pyrrolidinyl norephedrine as such pure product that it may be used as a solution stream reagent in the chiral addition of lithium cyclopropylacetylide. The present invention provides the preparation of cyclopropylacetylene as such pure product that it too may be used as a solution stream reagent in the chiral addition of the cyclopropylacetylide anion, for example, lithium cyclopropylacetylide.
The present invention provides an improved synthetic process for the asymmetric synthesis of benzoxazinones. The process of the present invention eliminates the use of highly toxic ceric ammonium nitrate, thus eliminating cerium ions in the waste stream. The present invention provides for an efficient non-chromatographic purification process to yield enantiomericly pure product. Additionally, the present invention provides for intermediates as stable solids purifiable by recrystallization.
None of the above-cited references describe the methods of the present invention for the synthesis of benzoxazinones useful as inhibitors of HIV reverse transcriptase.